TECHNICAL FIELD
[0001] This disclosure relates to endoprostheses with a luminal surface, at least a portion
of which is covered with a first coating including a first drug, and an abluminal
surface, at least a portion of which is covered with a second coating including a
second drug, wherein the first coating is formed of a bio-stable matrix material and
the second coating is formed of a biodegradable matrix material.
BACKGROUND
[0002] The body includes various passageways such as arteries, other blood vessels, and
other body lumens. These passageways sometimes become occluded or weakened. For example,
the passageways can be occluded by a tumor, restricted by plaque, or weakened by an
aneurysm. When this occurs, the passageway can be reopened or reinforced with a medical
endoprosthesis. An endoprosthesis is typically a tubular member that is placed in
a lumen in the body. Examples of endoprostheses include stents, covered stents, and
stent-grafts.
[0003] Endoprostheses can be delivered inside the body by a catheter that supports the endoprosthesis
in a compacted or reduced-size form as the endoprosthesis is transported to a desired
site. Upon reaching the site, the endoprosthesis is expanded, e.g., so that it can
contact the walls of the lumen. Stent delivery is further discussed in Heath,
U.S. 6,290,721.
[0004] The expansion mechanism may include forcing the endoprosthesis to expand radially.
For example, the expansion mechanism can include the catheter carrying a balloon,
which carries a balloon-expandable endoprosthesis. The balloon can be inflated to
deform and to fix the expanded endoprosthesis at a predetermined position in contact
with the lumen wall. The balloon can then be deflated, and the catheter withdrawn
from the lumen.
[0005] Passageways containing endoprostheses can become re-occluded. Re-occlusion of such
passageways is known as restenosis. It has been observed that certain drugs can inhibit
the onset of restenosis when the drug is contained in the endoprosthesis. It is sometimes
desirable for an endoprosthesis-contained therapeutic agent, or drug to elute into
the body fluid in a predetermined manner once the endoprosthesis is implanted.
SUMMARY
[0006] In an aspect, the invention features an endoprosthesis having a luminal surface,
at least a portion of which is covered with a first coating including a first drug,
and an abluminal surface, at least a portion of which is covered with a second coating
including a second drug. The first drug has a first eluting profile based on the first
coating, and the second drug has a second eluting profile based on the second coating,
the first eluting profile being different from the second eluting profile. The first
coating is formed of a bio-stable matrix material, and the second coating is formed
of a biodegradable matrix material. The first and second coatings can be substantially
free of polymer.
[0007] In another aspect, the invention features a method of forming an endoprosthesis that
includes forming a first coating of a bio-stable material having a first drug on a
luminal surface of the endoprosthesis, and forming a second coating of a biodegradable
material having a second drug over a abluminal surface of the endoprosthesis. The
first drug has a first eluting profile based on the first coating, and the second
drug has a second eluting profile based on the second coating, the first eluting profile
being different from the second eluting profile.
[0008] Embodiments may include one or more of the following features. The first coating
has a thickness of about 200 nm or less. The first drug is embedded in the bio-stable
matrix material. The first drug is an anti-coagulant: The anti-coagulant is heparin.
The first drug and the bio-stable matrix material have a volume ratio of about 1 to
2 to about 3 to 2. The second drug is embedded in the biodegradable matrix material.
The second drug is an anti-proliferative drug. The second drug is selected from paclitaxel,
everolimus, tacrolimus, and sirolimus. The second drug and the biodegradable matrix
material have a volume ratio of about 1 to 2 to about 3 to 2. The bio-stable matrix
material has interconnected pores. The pores have a size of about 1-30 nm in diameter.
The bio-stable matrix material is a metal, a metal nitride, or a metal oxide. The
bio-stable metal is selected from silver, platinum, gold, and a mixture thereof. The
bio-stable metal oxide or nitride is selected from oxide or nitride of iridium, zirconium,
titanium, hafnium, niobium, tantalum, ruthenium, platinum, and a mixture thereof.
The bio-stable metal oxide is iridium oxide. The bio-stable metal oxide or nitride
has a smooth globular surface morphology to enhance endothelial cell growth on the
oxide or the nitride. The biodegradable matrix material is a metal, or a metal salt.
The biodegradable metal is selected from magnesium, calcium, aluminum, iron, zinc,
titanium, and a mixture thereof. The biodegradable metal salt is selected from magnesium
oxide, magnesium fluoride, tricalcium phosphate, calcium carbonate, and a mixture
thereof. The biodegradable metal salt is tricalcium phosphate. The first coating is
formed of a first bio-stable matrix material and the second coating is formed of a
biodegradable material and a second bio-stable matrix material between the biodegradable
material and the abluminal surface, where the first and the second bio-stable matrix
materials are the same or different materials.
[0009] Embodiments may also include one or more of the following features. The bio-stable
material and the first drug are co-deposited on the first region by pulsed laser deposition
("PLD"). The biodegradable material and the second drug are co-deposited on the second
region by PLD. The bio-stable material is a metal, a metal nitride, or a metal oxide.
The bio-stable metal oxide or nitride is selected from oxide or nitride of iridium,
zirconium, titanium, hafnium, niobium, tantalum, ruthenium, platinum, and a mixture
thereof. The bio-stable metal oxide is iridium oxide. The bio-stable metal oxide or
nitride has a smooth globular surface morphology to enhance endothelial cell growth.
The biodegradable material is a metal or a metal salt. The biodegradable metal salt
is selected from magnesium oxide, magnesium fluoride, tricalcium phosphate, calcium
carbonate, and a mixture thereof. The biodegradable metal salt is tricalcium phosphate.
The first and second drugs are in the form of nano-sized particles. The nano-sized
drug particles are coated by PLD using pneumatic fluidization.
[0010] Embodiments may include one or more of the following advantages. Stents can be formed
with selective coating materials (e.g. as drug carriers) on select portions, such
as the abluminal and luminal surfaces, to achieve different desirable functions on
different portions of the stent. For example, it may be desirable that the luminal
side or the blood-facing side of the stent be covered only by a thin layer of endothelial
cells while the abluminal side or the tissue-facing side of the stent have a surface
with low level of irritation or none to the surrounding tissues. Accordingly, the
coating material overlying the luminal stent surface is formed of a bio-stable inorganic
compound or ceramic, e.g., IROX, which has therapeutic advantages such as reducing
the likelihood of restenosis and enhancing endothelial cell growth. The morphologies
of the coating material can be selected to control the therapeutic properties of the
coating and/or the porosity of the coating can be controlled to provide a desired
drug release profile over an extended period. In comparison, the coating material
overlying the abluminal stent surface is formed of a biodegradable inorganic compound,
e.g., magnesium, tricalcium phosphate ("TCP"), or magnesium fluoride, which is capable
of dissolving or being absorbed in a biological environment and thus capable of accelerating
the release rate of a drug embedded in the coating material at the beginning after
the stent implantation, for instance. The coating materials are substantially free
of polymers, therefore avoiding any adverse effects caused by polymers such as acute
or late thrombosis caused by polymer delamination. In addition, different drugs can
be included in the abluminal and luminal coating materials to obtain predetermined
therapeutic effects at different portions of the stent. For example, anti-proliferative
drugs such as paclitaxel (PTX), Everolimus, and Tacrolimus, can be loaded in the abluminal
coating material while anti-coagulants (e.g., Heparin) can be loaded in the luminal
coating material. The coating materials and drugs can be selectively formed on the
desired portions of the stent by low temperature deposition process, such as PLD,
which reduce the likelihood of degradation of drugs by heat. Moreover, PLD enables
the co-deposition of the coating materials and drugs and thus various drug-loading
procedures after the formation of the drug carriers or reservoirs can be avoided.
The coatings can also accommodate a large quantity of drugs and at the same time relatively
thin.
[0011] Still further aspects, features, embodiments, and advantages follow.
DESCRIPTION OF DRAWINGS
[0012]
FIGS. 1A-1C are longitudinal cross-sectional views illustrating delivery of a stent
in a collapsed state, expansion of the stent, and deployment of the stent.
FIG. 2 is a perspective view of a stent.
FIG. 3 is a cross-sectional schematic of a portion of a stent wall.
FIGS. 3A and 3B show different drug release profiles obtained at the abluminal and
luminal sides of a stent by forming different coating materials on respective stent
surfaces.
FIG. 4 is a cross-sectional schematic of drug elution.
FIG. 5 is a flow diagram illustrating manufacture of a stent.
FIG. 6 is a schematic of a PLD system.
FIGS. 7A-7C are FESEM images: FIG. 7A and 7B are enlarged plan views of a stent wall
surface, FIG. 7C is an enlarged cross-sectional view of a stent wall surface.
FIGS. 8A-8C are schematics of ceramic morphologies..
FIG. 9 is a schematic of another embodiment of coating a stent.
DETAILED DESCRIPTION
[0013] Referring to FIGS. 1A-1C, a stent 20 is placed over a balloon 12 carried near a distal
end of a catheter 14, and is directed through the lumen 16 (FIG. 1A) until the portion
carrying the balloon and stent reaches the region of an occlusion 18. The stent 20
is then radially expanded by inflating the balloon 12 and compressed against the vessel
wall with the result that occlusion 18 is compressed, and the vessel wall surrounding
it undergoes a radial expansion (FIG. 1B). The pressure is then released from the
balloon and the catheter is withdrawn from the vessel (FIG. 1C).
[0014] Referring to FIG. 2, the stent 20 includes a plurality of fenestrations 22 defined
in a wall 23. Stent 20 includes several surface regions, including an outer, or abluminal,
surface 24, an inner, luminal, surface 26, and a plurality of cutface surfaces 28.
The stent can be balloon expandable, as illustrated above, or a self-expanding stent.
Examples of stents are described in Heath `721,
supra.
[0015] Referring to FIG. 3, a cross-sectional view, a stent wall 23 includes a stent body
25 formed, e.g. of a metal or a polymer; a luminal surface 26, at least part of which
is covered by a first coating material 32, a bio-stable or permanent matrix, with
a first drug 33 (illustrated as crosses) embedded therein; and an abluminal surface
24, at least part of which is covered by a second coating material 34, a biodegradable
matrix, with a second drug 35 (illustrated as open circles) embedded therein. The
first and second coating materials are different, e.g., their physical and/or chemical
structures and properties in a biological environment can be different. The first
and second drugs can be the same or different therapeutic agents.
[0016] In embodiments, the first coating and second coating materials are both non-polymeric
materials such as inorganic compounds, e.g., metal, metal salts, metal oxides, nitrides,
and halides, etc. The coating materials can also be selected from biological substances
that primarily consist of inorganic compounds such as shells, bones, pearl, and corals.
[0017] The first coating material 32 is a bio-stable or permanent non-polymeric material,
such as iridium oxide ("IROX"), which can have therapeutic advantages such as enhancing
growth of a thin layer of endothelial cells as well as accommodating sufficient amounts
of drug. The first drug 33 can be an anti-coagulant such as heparin. In embodiments,
the bio-stable materials have porous structures, e.g., interconnected pores that can
form channels for drug to elute into the surrounding biological environment. In embodiments,
the first coating material or matrix with embedded first drug can form a layer on
the luminal surface by a physical vapor deposition ("PVD") process. The layer has
a thickness of about 10 nm to about 1000 nm, e.g., about 50-500nm, or about 100nm.
In embodiments, the volume ratio of the drug and the matrix is about 1:2, or more,
e.g. about 1:1 or more, e.g. about 3:2. In particular embodiment, the volume ratio
of drug and matrix can vary at different depths of the coating, e.g., from 3:2 at
an outermost surface of the coating to 1:2 at the coating/stent interface. In embodiments,
the first coating material or the matrix has a pore size of about 1 to 30 nm. In particular
embodiments, the bio-stable or permanent coating 32 are formed of an inorganic compound
such as a metal (e.g., silver, platinum, iridium, zirconium, titanium, hafnium, niobium,
tantalum or ruthenium, or gold), a metal oxide or a ceramic, such as iridium oxide
("IROX"), titanium oxide ("TiO
x"), silicon oxide ("silica") or oxides of niobium ("Nb"), tantalum ("Ta"), ruthenium
("Ru") or mixture thereof. Without wishing to be bound by theory, it is believed that
certain ceramics, e.g. oxides, can reduce restenosis, e.g., through the catalytic
reduction of hydrogen peroxide and other precursors to smooth muscle cell proliferation,
or their superior hemocompatibility. The oxides can also encourage endothelial growth
to enhance endothelialization of the stent. When a stent is introduced into a biological
environment (e.g., in vivo), one of the initial responses of the human body to the
implantation of a stent, particularly into the blood vessels, is the activation of
leukocytes, white blood cells which are one of the constituent elements of the circulating
blood system. This activation causes an increase of reactive oxygen compound production.
One of the species released in this process is hydrogen peroxide, H
2O
2, which is released by neutrophil granulocytes, which constitute one of the many types
of leukocytes. The presence of H
2O
2 may increase proliferation of smooth muscle cells and compromise endothelial cell
function, stimulating the expression of surface binding proteins which enhance the
attachment of more inflammatory cells. A ceramic, such as IROX can catalytically reduce
H
2O
2. The morphology of the ceramic can enhance the catalytic effect and reduce proliferation
of smooth muscle cells. In a particular embodiment, IROX is selected to form the coating
32, which can have therapeutic benefits such as enhancing endothelialization. IROX
and other ceramics are discussed further in
Alt et al., U.S. Patent No. 5,980,566,
USSN 10/651,562 filed August 29, 2003, and in
Huang et al., Biomaterials 24 (2003): 2177-2187.
[0018] The second coating material 34 is a non-polymeric biodegradable material, such as
a biodegradable metal, e.g., magnesium, iron, tungsten, or calcium, or a metal salt
e.g., tricalcium phosphate (Ca
3(PO
4)
2 or TCP), calcium carbonate, biodegradable Hydroxyapatite (Ca
10(PO
4)
6(OH)
2 or HA) e.g., nanocrystalline HA, or magnesium fluoride, and the second drug 35 can
be restenosis inhibitors or anti-proliferative drugs including paclitaxel ("PTX")
or Everolimus. The bio-degradable coating can have either a porous structure or a
nonporous structure. In embodiments, the second coating material or matrix with embedded
second drug can form a layer on the abluminal surface by a physical vapor deposition
("PVD") process as well. The layer has a thickness of about 10 nm to about 1000 nm,
e.g., about 50-500nm, or about 100nm. In embodiments, the volume ratio of the drug
and the matrix is about 1:2, or more, e.g. about 1:1 or more, e.g. about 3:2. In particular
embodiment, the volume ratio of drug and matrix can vary at different depths of the
coating, e.g., from 1:2 at outmost surface of the coating to 3:2 at the coating/stent
interface. Hydroxyapatite is discussed further in
Kilian et al., Biomaterials 26 (2005): 1819-1827.
[0019] In embodiments, the discriminating selection of coating materials and/or drugs on
different portions of the stent allows different desirable functions on different
portions of the stent. For example, the luminal surface or the blood-facing side of
the stent coated with the first coating material (e.g., IROX) can be covered only
by a thin layer of endothelial cells while the abluminal surface or the tissue-facing
side of the stent coated with the second coating material (e.g., TCP) can provide
a surface with low level of irritation or none to the surrounding tissues. Moreover,
in particular embodiments, different drug release profiles of different portions of
the stent can also be achieved by selecting different coating materials. Referring
particularly to FIGS. 3A and 3B, different drug release profiles at the abluminal
and luminal sides of a stent can be obtained by forming different coating materials
on respective stent surfaces. For example, FIG. 3A shows a predetermined PTX release
profile in a biodegradable matrix at, e.g. the abluminal stent surface. The initial
burst of PTX elution can be attributed to the biodegradable matrix erosion that leads
to increasing exposure of PTX embedded in the matrix. FIG. 3B shows a different release
profile of an anti-coagulant in an IROX matrix at, e.g. the luminal stent surface.
In comparison, the relative steady release rate of a drug in a bio-stable matrix (e.g.,
IROX) can be attributed to the biostability of the matrix and its porous structure.
In embodiments, drug release profile can also be selected by controlling the drug
content or concentration at different depth of the matrix. For example, higher drug
content at the outer surface of matrix will generate a release profile with an initial
burst of drug release while higher drug content in a deeper layer of matrix will produce
a release profile with a late burst.
[0020] In some embodiments, certain portions of the stent may have multiple coating materials,
for example, the abluminal surface of the stent can have both the first and the second
coating materials. Referring particularly to FIG. 4, both the abluminal and luminal
surfaces are coated with the first material 32, e.g., IROX, and the first drug 33,
e.g. an anti-coagulant, and only the abluminal surface has the second coating material
34, e.g., a non-polymeric biodegradable material, and the second drug 35, e.g., PTX,
on top of the first coating. The first and the second drugs can be different or the
same compounds. In still some embodiments, there may be multiple drugs in one coating
matrix.
[0021] Referring to FIG. 5, a medical device, e.g., a stent is formed by first providing
the first coating materialt, e.g. a bio-stable material, and a first drug on the device
(step 51) by a technique that uses low temperature to reduce the likelihood of damaging
the drug, such as pulsed layer deposition ("PLD"). Next, the coating of desired region(s)
or surface(s) of the device can be optionally removed (step 52) by, e.g., laser ablation
or argon ion milling processes. Finally, a second coating material, e.g., a biodegradable
material, and a second drug are provided over the desired region(s) or surface(s)
(step 53) by a technique that uses low temperature to reduce the likelihood of damaging
the drug, such as PLD.
[0022] In a particular embodiment, all the surfaces of a stent (e.g., abluminal, luminal
and cutface surfaces) are initially coated with a first coating material through co-deposition
of IROX and Heparin particles without any mask. In a following step, a desired region,
e.g., the luminal surface of the stent is masked or shielded by, e.g., a central metal
stick or mandrel that supports the stent while the other surfaces are subjected to
removal of the first coating via, e.g., ion milling, laser ablation or evaporation,
so that the stent body can be revealed in those regions for a different coating. The
stent, still masked on the same region, e.g., the luminal side, is then coated with
a second coating material through co-deposition of a biodegradable matrix, e.g., TCP
and PTX or Everolimus particles. The stent as produced will have a coating structure
close to that illustrated in FIG. 3. In another particular embodiment, when the same
procedure as described above has been followed except that no removing step is involved,
the stent as produced will have a coating structure close to that illustrated in FIG.
4.
[0023] Referring particularly to steps 51 and 53 in FIG. 5, in embodiments, the first (or
second) coating material or matrix and the first (or second) drug are provided over
the stent surfaces by a technique that uses low temperature to reduce the likelihood
of damaging the drug, such as PLD. One suitable class of PLD can be inverse PLD, which
is discussed in
Egerhazi et al., Applied Surface Science 247, 182-187 (2005). Referring to FIG. 6, the PLD system 60 includes a chamber 62 in which is provided
a target assembly 64 and a stent substrate 66, such as a stent body or a pre-stent
structure such as a metal tube. The target assembly includes a first target material
68, such as a bio-stable material (e.g., IROX), or a precursor to such a material
(e.g., iridium metal), or a biodegradable material such as bio-erodible metal (e.g.
magnesium) or salt (e.g. TCP), or naturally available biological substances such as
shells, bones, pearl, and corals, and a second target material 70 such as a drug,
e.g., an anti-coagulant or an anti-proliferative drug. Laser energy (double arrows)
is selectively directed onto the target materials to cause the target materials to
be ablated or sputtered from the target assembly. The sputtered material (often known
as a laser-produced plasma plume, which is in the form of small clusters, e.g., neutrals,
ions, electrons etc.) is imparted with kinetic energy in the ablation process such
that the material is transported within the chamber (single arrows) and deposited
on the stent 66. In addition, the temperature of the deposited material can be controlled
by heating, e.g. using an infrared source (squiggly arrows).
[0024] The composition of the deposited materials (e.g., the relative abundance of the matrix
and the drug) is selected by control of the deposition process. For example, the composition
of the deposited materials is selected by controlling the exposure of the target materials
to laser energy. To deposit pure matrix or pure drug, only the matrix or the drug
target is exposed to laser energy. To deposit a composite layer of matrix and drug,
both target materials are exposed simultaneously or alternately exposed in rapid succession.
The relative amount of matrix material and drug is controlled by the laser energy
and/or exposure time. For example, drug content in the matrix-drug composite layers
can be controlled to vary gradually over the depth of the coating layers or to vary
according to a predetermined release profile. In embodiments, the drug and matrix
materials are deposited as small clusters, e.g., 200nm or less, such as 1-10nm, and
preferably smaller than the gross morphological features of the layers.
[0025] In particular embodiments, the laser energy is produced by an excimer laser operating
in the ultraviolet, e.g. at a wavelength of about 248 nm. The laser energy is about
100-700 mJ, the fluence is in the range of about 10 to 50 mJ/cm
2. The background pressure is in the range of about 1E-5 mbar to 1 mbar. The background
gas includes oxygen. The substrate temperature is also controlled. The temperature
of the substrate is between about 25 to about 300°C during deposition. In some embodiments,
the temperature of the substrate is selected to be lower then the drug decomposition
temperature, e.g., less than about 200°C, or even less than 100°C. Substrate temperature
can be controlled by directing an infrared beam onto the substrate during deposition
using, e.g. a halogen source. The temperature is measured by mounting a heat sensor
in the beam adjacent the substrate. The temperature can be varied to control the morphology
of the matrix material. The selective ablating of the matrix or drug is controlled
by mounting the target materials on a moving assembly that can alternately bring the
materials into the path of the laser. Alternatively, a beam splitter and shutter can
be used to alternatively or simultaneously expose multiple materials. PLD deposition
services are available from Axyntec (Augsburg, Germany). Suitable matrix materials
include biostable or biodegradable ceramics, e.g. metal oxides and nitrides, such
as of iridium, zirconium, titanium, hafnium, niobium, tantalum, ruthenium, platinum,
calcium, magnesium, and aluminum. In embodiments, the thickness of the coatings is
in the range of about 50 nm to about 2 um, e.g. 100 nm to 500 nm. Pulsed laser deposition
is also described in
application USSN 11/752,736, filed May 23, 2007 [Attorney Docket No. 10527-801001]. In other embodiments, another physical vapor
deposition ("PVD") process is selected such as magnetron sputtering e.g. an iridium
target under an oxygen atmosphere or an IROX target. Sputtering deposition is described
in application
USSN 11/752,772, filed May 23, 2007 [Attorney Docket No. 10527-805001].
[0026] In particular embodiments, the bio-stable matrix coatings have surfaces with a select
roughness or morphology as described in
USSN 11/752,736,
USSN 11/752,772, and appendices, supra. Referring to FIGS. 7A and 7B, the morphology of the bio-stable
matrix such as a ceramic (e.g., IROX) can be varied between relatively rough surfaces
and relatively smooth surfaces, which can each provide particular mechanical and therapeutic
advantages, such as a controlled porosity to modulate drug release from the matrix.
Referring particularly to FIG. 7A, a ceramic coating can have a morphology characterized
by defined grains and high roughness. Referring particularly to FIG. 7B, a ceramic
coating can have a morphology characterized by a higher coverage, globular surface
of generally lower roughness. The defined grain, high roughness morphology provides
a high surface area characterized by crevices between and around spaced grains into
which, e.g., a polymer coating can be deposited and interlock to the surface, greatly
enhancing adhesion. Defined grain morphologies also allow for greater freedom of motion
and are less likely to fracture as the stent is flexed in use and thus the matrix
coating resists delamination of the ceramic from an underlying surface and reduces
delamination of a possible overlaying coating. The stresses caused by flexure of the
stent during expansion or contraction of the stent or as the stent is delivered through
a tortuously curved body lumen increase as a function of the distance from the stent
axis. As a result, in embodiments, a morphology with defined grains is particularly
desirable on abluminal regions of the stent or at other high stress points, such as
the regions adjacent fenestrations which undergo greater flexure during expansion
or contraction. Smoother globular surface morphology provides a surface which is tuned
to facilitate endothelial growth by selection of its chemical composition and/or morphological
features. Certain ceramics, e.g. oxides, can reduce restenosis through the catalytic
reduction of hydrogen peroxide and other precursors to smooth muscle cell proliferation.
The oxides can also encourage endothelial cell growth to enhance endothelialization
of the stent. As discussed above, when a stent is introduced into a biological environment
(e.g., in vivo), one of the initial responses of the human body to the implantation
of a stent, particularly into the blood vessels, is the activation of white blood
cells. This activation causes a release of hydrogen peroxide, H
2O
2. The presence of H
2O
2 may increase proliferation of smooth muscle cells and compromise endothelial cell
function, stimulating the expression of surface binding proteins which enhance the
attachment of more inflammatory cells. A ceramic, such as IROX can catalytically reduce
H
2O
2. The smoother globular surface morphology of the ceramic can enhance the catalytic
effect and enhance growth of endothelial cells.
[0027] Referring particularly to FIG. 7C, a cross-sectional view of the ceramic layer with
surface morphology shown in FIG. 7B, channels formed of interconnected pores in the
ceramic are visible. In embodiments, the channels have a diameter selectively controlled
by deposition parameters as discussed above. The bigger the diameter, the faster the
drug release rate. In particular embodiments, the channel diameter is selected to
be about 10nm or less to control the drug release over a extended period of time.
[0028] The morphology of the ceramic is controlled by controlling the energy of the sputtered
clusters on the stent substrate. Higher energies and higher temperatures result in
defined grain, higher roughness surfaces. Higher energies are provided by increasing
the temperature of the ceramic on the substrate, e.g. by heating the substrate or
heating the ceramic with infrared radiation. In embodiments, defined grain morphologies
are formed at temperatures of about 250°C or greater. Globular morphologies are formed
at lower temperatures, e.g. ambient temperatures without external factors. The heating
enhances the formation of a more crystalline ceramic, which forms the grains. Intermediate
morphologies are formed at intermediate values of these parameters. The composition
of the ceramic can also be varied. For example, oxygen content can be increased by
providing oxygen gas in the chamber.
[0029] The morphology of the surface of the ceramic is characterized by its visual appearance,
its roughness, and/or the size and arrangement of particular morphological features
such as local maxima. In embodiments, the surface is characterized by definable sub-micron
sized grains. Referring particularly to FIG. 7A, for example, in embodiments, the
grains have a length, L, of about 50 to 500nm, e.g. about 100-300nm, and a width,
W, of about 5nm to 50nm, e.g. about 10-15nm. The grains have an aspect ratio (length
to width) of about 5:1 or more, e.g. 10:1 1 to 20:1. The grains overlap in one or
more layers. The separation between grains can be about 1-50 nm. In particular embodiments,
the grains resemble rice grains.
[0030] Referring particularly to FIG. 7B, in embodiments, the surface is characterized by
a more continuous surface having a series of shallow globular features. The globular
features are closely adjacent with a narrow minima between features. In embodiments,
the surface resembles an orange peel. The diameter of the globular features is about
100nm or less, and the depth of the minima, or the height of the maxima of the globular
function is, e.g., about 50nm or less, e.g. about 20nm or less. In other embodiments,
the surface has characteristics between high aspect ratio definable grains and the
more continuous globular surface and/or has a combination of these characteristics.
For example, the morphology can include a substantially globular base layer and a
relatively low density of defined grains. In other embodiments, the surface can include
low aspect ratio, thin planar flakes. The morphology type is visible in FESEM images
at 50 KX.
[0031] Referring to FIGS. 8A-8C, morphologies are also characterized by the size and arrangement
of morphological features such as the spacing, height and width of local morphological
maxima. Referring particularly to FIG. 8A, a coating 40 on a substrate 42 is characterized
by the center-to-center distance and/or height, and/or diameter and/or density of
local maxima. In particular embodiments, the average height, distance and diameter
are in the range of about 400 nm or less, e.g. about 20-200 nm. In particular, the
average center-to-center distance is about 0.5 to 2x the diameter.
[0032] Referring to FIG. 8B, in particular embodiments, the morphology type is a globular
morphology, the width of local maxima is in the range of about 100nm or less and the
peak height is about 20 nm or less. In particular embodiments, the ceramic has a peak
height of less than about 5 nm, e.g., about 1-5 nm, and /or a peak distance less than
about 15 nm, e.g., about 10-15 nm. Referring to FIG. 8C, in embodiments, the morphology
is defined as a grain type morphology. The width of local maxima is about 400 nm or
less, e.g. about 100-400 nm, and the height of local maxima is about 400 nm or less,
e.g. about 100-400 nm. As illustrated in FIGS. 8B and 8C, the select morphologies
of the ceramic can be formed on a thin layer of substantially uniform, generally amorphous
IROX, which is in turn formed on a layer of iridium metal, which is in turn deposited
on a metal substrate, such as titanium or stainless steel. The spacing, height and
width parameters can be calculated from AFM data.
[0033] The roughness of the surface is characterized by the average roughness, Sa, the root
mean square roughness, Sq, and/or the developed interfacial area ratio, Sdr. The Sa
and Sq parameters represent an overall measure of the texture of the surface. Sa and
Sq are relatively insensitive in differentiating peaks, valleys and the spacing of
the various texture features. Surfaces with different visual morphologies can have
similar Sa and Sq values. For a surface type, the Sa and Sq parameters indicate significant
deviations in the texture characteristics. Sdr is expressed as the percentage of additional
surface area contributed by the texture as compared to an ideal plane the size of
the measurement region. Sdr further differentiates surfaces of similar amplitudes
and average roughness. Typically Sdr will increase with the spatial intricacy of the
texture whether or not Sa changes.
[0034] In embodiments, the ceramic has a defined grain type morphology. The Sdr is about
30 or more, e.g. about 40 to 60. In addition or in the alternative, the morphology
has an Sq of about 15 or more, e.g. about 20 to 30. In embodiments, the Sdr is about
100 or more and the Sq is about 15 or more. In other embodiments, the ceramic has
a globular type surface morphology. The Sdr is about 20 or less, e.g. about 8 to 15.
The Sq is about 15 or less, e.g. about less than 8 to 14. In still other embodiments,
the ceramic has a morphology between the defined grain and the globular surface, and
Sdr and Sq values between the ranges above, e.g. an Sdr of about 1 to 200 and/or an
Sq of about 1 to 30.
[0035] The morphology of the ceramic coating can exhibit high uniformity. The uniformity
provides predictable, tuned therapeutic and mechanical performance of the ceramic.
The uniformity of the morphology as characterized by Sa, Sq or Sdr and/or average
peak spacing parameters can be within about +/- 20% or less, e.g. +/- 10% or less
within a 1 µm square. In a given stent region, the uniformity is within about +/-
10%, e.g. about +/- 1 %. For example, in embodiments, the ceramic exhibits high uniformity
over an entire surface region of stent, such as the entire abluminal or luminal surface,
or a portion of a surface region, such as the center 25% or 50% of the surface region.
The uniformity is expressed as standard deviation. Uniformity in a region of a stent
can be determined by determining the average in five randomly chosen 1 µm square regions
and calculating the standard deviation. Uniformity of a morphology type in a region
is determined by inspection of FESEM data at 50 kx.
[0036] The ceramics are also characterized by surface composition, composition as a function
of depth, and crystallinity. In particular, the amounts of oxygen or nitride in the
ceramic is selected for a desired catalytic effect on, e.g., the reduction of H
2O
2 in biological processes. The composition of metal oxide or nitride ceramics can be
determined as a ratio of the oxide or nitride to the base metal. In particular embodiments,
the ratio is about 2 to 1 or greater, e.g. about 3 to 1 or greater, indicating high
oxygen content of the surface. In other embodiments, the ratio is about 1 to 1 or
less, e.g. about 1 to 2 or less, indicating a relatively low oxygen composition. In
particular embodiments, low oxygen content globular morphologies are formed to enhance
endothelialization. In other embodiments, high oxygen content defined grain morphologies
are formed, e.g., to enhance adhesion and catalytic reduction. Composition can be
determined by x-ray photoelectron spectroscopy (XPS). Depth studies are conducted
by XPS after fast atomic beam ("FAB") sputtering. The crystalline nature of the ceramic
can be characterized by crystal shapes as viewed in FESEM images, or Miller indices
as determined by x-ray diffraction. In embodiments, defined grain morphologies have
a Miller index of <101>. Globular materials have blended amorphous and crystalline
phases that vary with oxygen content. Higher oxygen content typically indicates greater
crystallinity.
[0037] In embodiments, the ceramic is deposited directly onto the metal surface of a stent
body, e.g. a stainless steel, without the use of an intermediate metal layer. In other
embodiments, a layer of metal common to the ceramic is deposited onto the stent body
before deposition to the ceramic. For example, a layer of iridium may be deposited
onto the stent body, followed by deposition of IROX onto the iridium layer. Other
suitable ceramics, e.g., bio-stable ceramics, include metal oxides and nitrides, such
as of iridium, zirconium, titanium, hafnium, niobium, tantalum, ruthenium, and platinum.
The ceramic can be crystalline, partly crystalline or amorphous. The ceramic can be
formed entirely of inorganic materials or a blend of inorganic and organic material
(e.g. a polymer). In other embodiments, the morphologies described herein can be formed
of metal.
[0038] In another particular embodiment, the coating steps, e.g., steps 51 and 53 of FIG.
5 can use a PLD system as illustrated in FIG. 9. The PLD system allows coating solid
nano-sized drug particles as a core material with a substance that is laser-ablated
from a solid target material (polymer, oxide, etc.) under a pneumatic fluidization
condition. In this embodiment, the drug particles are pre-formed before being placed
in the PLD system while in the co-deposition process discussed above the drug clusters
are formed in situ. The drug particles are about 1 micron or less at their largest
dimension, e.g. 500nm or less. Suitable small particles, e.g. of paclitaxel, are available
from Pharmasol GMBH (Blohmst 66 A, 12307 Berlin, Germany). Coating drug particles
before depositing the drug onto a substrate, e.g. stent, may stabilize drug particles
and further reduce the likelihood of drug damaging through PLD processes. A suitable
PLD system is described in
Talton, U.S. Pat. No. 7,063,748.
[0039] The drug coating material (i.e., material used to coat the drug particles) can be
the matrix material, e.g., bio-stable or biodegradable inorganic compounds as discussed
above. In other cases, the drug coating material can be a polymer. Suitable polymers
include, for example, cellulose, polyacrylate, degradable polyester, copolymers with
vinyl monomers such as isobutylene, isoprene and butadiene, for example, styrene-isobutylene-styrene
(SIBS), styrene-isoprene-styrene (SIS) copolymers, styrenebutadiene-styrene (SBS)
copolymers. Other suitable polymers, including biodegradable and non-biodegradable
polymers, are discussed in
U.S. Pat. No. 7,063,748 and
USSN 11/752,736, filed May 23, 2007 [Attorney Docket No. 10527-801001]. The drug coating is on the order of from about
10 to about 1000 nm thick, preferably about 10 to 500 nm thick.
[0040] Referring particularly to FIG. 9, the apparatus is a top-coating apparatus 1 which
includes a coating chamber 2, formed from a cylindrical portion 5 connected to a conical
portion 3. Conical portion 3 is connected at its tapered end to a gas-permeable porous
plate 7, and a gas distributor 9, adjacent to plate 7. At the opposite end of cylindrical
portion 5, a filter 11 with cylindrical housing is mounted. An exhaust duct 13 carries
gas for recirculation back through a filter assembly 15, through a blower (not shown),
a temperature controller 17, then back to gas distributor 9 before re-entering the
chamber. Top-coating apparatus 1 also includes an external evaporation or removal
source (e.g., laser) 21, which is directed upward into central chamber 2 through window
23 to the matrix target (MT) 25, e.g., IROX, TCP, or SIBS, at approximately a 45 degree
angle. Window 23 is formed from an optically transparent material, which is preferably
quartz. The plume 27 leaves MT 25 downward toward the fluidized particles 41 below
MT 25. Plume 27 coats onto core particles 41 which are contacted. The core particles
41, e.g., nano-sized drug particles, are preferably fluidized within the coating chamber
to improve the uniformity of coating. An external control device 31 and container
33 are used to feed or turn MT 25, which may involve a rotating motor control and/or
feeding tube. Container 33 may also include a chiller to freeze material for MT 25.
A mechanical vibrator 45 can be used in conjunction with the gas fluidization to prevent
particle agglomeration and to apply fluidization at lower gas flow regimes. The fluidization
is preferably achieved by air/gas stream fluidization. That is, the core particles,
e.g. drug particles, are placed in the path of flowing air or gas, which fluidizes
the cores, improving their mixing and exposure to the coating chamber atmosphere.
[0041] Endoprostheses, e.g., stents, can be placed somewhere between the plume 27 and the
plate 7, e.g., arrow 43, without blocking the fluidizing path or compromising coating
of drug particles. The coated drug particles that are imparted with kinetic energies
of the ablated matrix material as well as of fluidizing air/gas stream can then deposit
on desired portions of the stent. The matrix material deposited on top of the coated
drug can further secure the drug particles that coat the stent in place. In other
embodiments, the coated drug particles can be deposited on the stent by applying optical
forces , e.g., using optical tweezers, more detail of which is provided in
Weber, US2005/0196614 A1, published September 8, 2005.
[0042] The terms "therapeutic agent", "pharmaceutically active agent", "pharmaceutically
active material", "pharmaceutically active ingredient", "biologically active substance
", "drug" and other related terms may be used interchangeably herein and include,
but are not limited to, small organic molecules, peptides, oligopeptides, proteins,
nucleic acids, oligonucleotides, genetic therapeutic agents, non-genetic therapeutic
agents, vectors for delivery of genetic therapeutic agents, cells, and therapeutic
agents identified as candidates for vascular treatment regimens, for example, as agents
that reduce or inhibit restenosis. By small organic molecule is meant an organic molecule
having 50 or fewer carbon atoms, and fewer than 100 non-hydrogen atoms in total.
[0043] Exemplary therapeutic agents include, e.g., anti-thrombogenic agents (e.g., heparin);
anti-proliferative/anti-mitotic agents (e.g., paclitaxel, 5-fluorouracil, cisplatin,
vinblastine, vincristine, inhibitors of smooth muscle cell proliferation (e.g., monoclonal
antibodies), and thymidine kinase inhibitors); antioxidants; anti-inflammatory agents
(e.g., dexamethasone, prednisolone, corticosterone); anesthetic agents (e.g., lidocaine,
bupivacaine and ropivacaine); anti-coagulants; antibiotics (e.g., erythromycin, triclosan,
cephalosporins, and aminoglycosides); agents that stimulate endothelial cell growth
and/or attachment. Therapeutic agents can be nonionic, or they can be anionic and/or
cationic in nature. Therapeutic agents can be used singularly, or in combination.
Preferred therapeutic agents include inhibitors of restenosis (e.g., paclitaxel),
immunosuppressants(e.g., everolimus, tacrolimus, Sirolimus), anti-proliferative agents
(e.g., cisplatin), and antibiotics (e.g., erythromycin). Additional examples of therapeutic
agents are described in
U.S. Published Patent Application No. 2005/0216074. Polymers for drug elution coatings are also disclosed in
U.S. Published Patent Application Nos. 2005/0019265 and
2005/0251249. A functional molecule, e.g. an organic, drug, polymer, protein, DNA, and similar
material can be incorporated into groves, pits, void spaces, and other features of
the ceramic.
[0044] Any stent described herein can be dyed or rendered radiopaque by addition of, e.g.,
radiopaque materials such as barium sulfate, platinum or gold, or by coating with
a radiopaque material. The stent can include (e.g., be manufactured from) metallic
materials, such as stainless steel (e.g., 316L, BioDur® 108 (UNS S29108), and 304L
stainless steel, and an alloy including stainless steel and 5-60% by weight of one
or more radiopaque elements (e.g., Pt, Ir, Au, W) (PERKS®) as described in
US2003/0018380 A1,
US2002/0144757 A1, and
US2003/0077200 A1), Nitinol (a nickel-titanium alloy), cobalt alloys such as Elgiloy, L605 alloys,
MP35N, titanium, titanium alloys (e.g., Ti-6A1-4V, Ti-50Ta, Ti-10Ir), platinum, platinum
alloys, niobium, niobium alloys (e.g., Nb-1Zr) Co-28Cr-6Mo, tantalum, and tantalum
alloys. Other examples of materials are described in commonly assigned
U.S. Application No. 10/672,891, filed September 26, 2003; and
U.S. Application No. 11/035,316, filed January 3, 2005. Other materials include elastic biocompatible metal such as a superelastic or pseudo-elastic
metal alloy, as described, for example, in
Schetsky, L. McDonald, "Shape Memory Alloys", Encyclopedia of Chemical Technology
(3rd ed.), John Wiley & Sons, 1982, vol. 20. pp. 726-736; and commonly assigned
U.S. Application No. 10/346,487, filed January 17, 2003.
[0045] The stents described herein can be configured for vascular, e.g. coronary and peripheral
vasculature or non-vascular lumens. For example, they can be configured for use in
the esophagus or the prostate. Other lumens include biliary lumens, hepatic lumens,
pancreatic lumens, urethral lumens.
[0046] The stent can be of a desired shape and size (e.g., coronary stents, aortic stents,
peripheral vascular stents, gastrointestinal stents, urology stents, tracheal/bronchial
stents, and neurology stents). Depending on the application, the stent can have a
diameter of between, e.g., about 1 mm to about 46 mm. In certain embodiments, a coronary
stent can have an expanded diameter of from about 2 mm to about 6 mm. In some embodiments,
a peripheral stent can have an expanded diameter of from about 4 mm to about 24 mm.
In certain embodiments, a gastrointestinal and/or urology stent can have an expanded
diameter of from about 6 mm to about 30 mm. In some embodiments, a neurology stent
can have an expanded diameter of from about 1 mm to about 12 mm. An abdominal aortic
aneurysm (AAA) stent and a thoracic aortic aneurysm (TAA) stent can have a diameter
from about 20 mm to about 46 mm. The stent can be balloon-expandable, self-expandable,
or a combination of both (e.g.,
U.S. Patent No. 6,290,721). The discriminating selection of different coatings and/or different drugs on different
regions, e.g., bio-stable coating on the blood-facing region and biodegradable coating
on the tissue-facing region, can be applied to other endoprostheses or medical devices,
such as catheters, guide wires, valves, and filters.
1. An endoprosthesis, comprising:
a luminal surface, at least a portion of which is covered with a first coating including
a first drug, the first drug having a first eluting profile based on the first coating,
and
an abluminal surface, at least a portion of which is covered with a second coating
including a second drug, the second drug having a second eluting profile based on
the second coating, the first eluting profile being different from the second eluting
profile, wherein the first coating is formed of a bio-stable matrix material and wherein
the second coating is formed of a biodegradable matrix material.
2. The endoprosthesis of claim 1, wherein the first and second coatings are free of polymer.
3. The endoprosthesis of claim 1, wherein the first coating has a thickness of 200 nm
or less.
4. The endoprosthesis of claim 1, wherein the first drug is embedded in the bio- stable
matrix material.
5. The endoprosthesis of claim 4, wherein the first drug is an anti-coagulant such as
heparin.
6. The endoprosthesis of claim 1, wherein the second drug is embedded in the biodegradable
matrix material.
7. The endoprosthesis of claim 6, wherein the second drug is an anti-proliferative drug
selected from paclitaxel, everolimus, tacrolimus, and sirolimus.
8. The endoprosthesis of claim 1, wherein the bio-stable matrix material has interconnected
pores.
9. The endoprosthesis of claim 8, wherein the bio-stable matrix material is a metal,
a metal nitride, or a metal oxide, the metal being selected from silver, platinum,
gold, iridium, zirconium, titanium, hafnium, niobium, tantalum, ruthenium, and a mixture
thereof, and the oxide or nitride being selected from oxide or nitride of iridium,
zirconium, titanium, hafnium, niobium, tantalum, ruthenium, platinum, and a mixture
thereof
10. The endoprosthesis of claim 9, wherein the oxide or nitride has a smooth globular
surface morphology to enhance endothelial cell growth on the oxide or the nitride.
11. The endoprosthesis of claim 1, wherein the biodegradable matrix material is a metal,
or a metal salt, the metal being selected from magnesium, calcium, aluminum, iron,
zinc, titanium, and a mixture thereof, and the metal salt being selected from magnesium
oxide, magnesium fluoride, tricalcium phosphate, calcium carbonate, and a mixture
thereof
12. The endoprosthesis of claim 1. wherein the first coating is formed of a first bio-stable
matrix material and the second coating is formed of a biodegradable material and a
second bio-stable matrix material between the biodegradable material and the ab luminal
surface, wherein the first and the second bio-stable matrix materials are the same
or different materials.
13. A method of forming an endoprosthesis, comprising:
forming a first coating of a bio-stable material having a first drug on a luminal
surface of the endoprosthesis so that the first drug has a first eluting profile based
on the first coating, and
forming a second coating of a biodegradable material having a second drug on an abluminal
surface of the endoprosthesis so that the second drug has a second eluting profile
based on the second coating, the first eluting profile being different from the second
eluting profile.
14. The method of claim 13, wherein the bio-stable material and the first drug are co-deposited
on the first region by PLD, or wherein the biodegradable material and the second drug
are co-deposited on the second region by PLD.
15. The method of claim 13, wherein the bio-stable material is a metal, a metal nitride,
or a metal oxide, the metal oxide or nitride being selected from oxide or nitride
of iridium, zirconium, titanium, hafnium, niobium, tantalum, ruthenium, platinum,
and a mixture thereof.
1. Endoprothese, umfassend:
eine luminale Oberfläche, wobei mindestens ein Teil dieser mit einer ersten Beschichtung
bedeckt ist, die einen ersten Wirkstoff beinhaltet, wobei der erste Wirkstoff ein
erstes Elutionsprofil hat, basierend auf der ersten Beschichtung, und
eine abluminale Oberfläche, wobei mindestens ein Teil dieser mit einer zweiten Beschichtung
bedeckt ist, die einen zweiten Wirkstoff beinhaltet,
wobei der zweite Wirkstoff ein zweites Elutionsprofil hat, basierend auf der zweiten
Beschichtung, wobei das erste Elutionsprofil unterschiedlich zu dem zweiten Elutionsprofil
ist, wobei die erste Beschichtung aus einem biostabilen Matrixmaterial gebildet ist
und wobei die zweite Beschichtung aus einem bioabbaubaren Matrixmaterial gebildet
ist.
2. Endoprothese nach Anspruch 1, wobei die ersten und zweiten Beschichtungen frei von
Polymer sind.
3. Endoprothese nach Anspruch 1, wobei die erste Beschichtung eine Dicke von 200 nm oder
weniger hat.
4. Endoprothese nach Anspruch 1, wobei der erste Wirkstoff in das biostabile Matrixmaterial
eingebettet ist.
5. Endoprothese nach Anspruch 4, wobei der erste Wirkstoff ein Antikoagulans wie zum
Beispiel Heparin ist.
6. Endoprothese nach Anspruch 1, wobei der zweite Wirkstoff in das bioabbaubaren Matrixmaterial
eingebettet ist.
7. Endoprothese nach Anspruch 6, wobei der zweite Wirkstoff ein antiproliferativer Wirkstoff
ist, ausgewählt aus Paclitaxel, Everolimus, Tacrolimus und Sirolimus.
8. Endoprothese nach Anspruch 1, wobei das biostabile Matrixmaterial miteinander verbundene
Poren hat.
9. Endoprothese nach Anspruch 8, wobei das biostabile Matrixmaterial ein Metall, ein
Metallnitrid oder ein Metalloxid ist, wobei das Metall ausgewählt ist aus Silber,
Platin, Gold, Iridium, Zirkon, Titan, Hafnium, Niob, Tantal, Ruthenium und einem Gemisch
daraus, und das Oxid oder Nitrid ausgewählt ist aus Oxid oder Nitrid von Iridium,
Zirkon, Titan, Hafnium, Niob, Tantal, Ruthenium, Platin und einem Gemisch daraus.
10. Endoprothese nach Anspruch 9, wobei das Oxid oder Nitrid eine glatte kugelförmige
Oberflächenmorphologie hat, um den endothelialen Zellwachstum auf dem Oxid oder Nitrid
zu steigern.
11. Endoprothese nach Anspruch 1, wobei das bioabbaubare Matrixmaterial ein Metall oder
ein Metallsalz ist, wobei das Metall ausgewählt ist aus Magnesium, Calcium, Eisen,
Zink, Titan, und einem Gemisch daraus, und das Metallsalz ausgewählt ist aus Magnesiumoxid,
Magnesiumfluorid, Tricalciumphosphat, Calciumcarbonat und einem Gemisch daraus.
12. Endoprothese nach Anspruch 1, wobei die erste Beschichtung aus einem ersten biostabilen
Matrixmaterial gebildet ist und die zweite Beschichtung aus einem bioabbaubaren Material
und einem zweiten biostabilen Matrixmaterial gebildet ist, zwischen dem bioabbaubaren
Material und der abluminalen Oberfläche, wobei die ersten und die zweiten biostabilen
Matrixmaterialien die gleichen oder verschiedene Materialien sind.
13. Verfahren zum Bilden einer Endoprothese, umfassend:
Bilden einer ersten Beschichtung aus einem biostabilen Material mit einem ersten Wirkstoff
auf einer luminalen Oberfläche der Endoprothese, so dass der erste Wirkstoff ein erstes
Elutionsprofil hat, basierend auf der ersten Beschichtung, und
Bilden einer zweiten Beschichtung aus einem bioabbaubaren Material mit einem zweiten
Wirkstoff auf einer abluminalen Oberfläche der Endoprothese, so dass der zweite Wirkstoff
ein zweites Elutionsprofil hat, basierend auf der zweiten Beschichtung, wobei das
erste Elutionsprofil unterschiedlich zu dem zweiten Elutionsprofil ist.
14. Verfahren nach Anspruch 13, wobei das biostabile Material und der erste Wirkstoff
gleichzeitig in der ersten Region mittels PLD abgeschieden werden, oder wobei das
bioabbaubare Material und der zweite Wirkstoff gleichzeitig in der zweiten Region
mittels PLD abgeschieden werden.
15. Verfahren nach Anspruch 13, wobei das biostabile Material ein Metall, ein Metallnitrid
oder ein Metalloxid ist, wobei das Metalloxid oder -nitrid ausgewählt ist aus Oxid
oder Nitrid von Iridium, Zirkon, Titan, Hafnium, Niob, Tantal, Ruthenium, Platin und
ein Gemisch daraus.
1. Endoprothèse, comprenant :
une surface luminale dont au moins une partie est recouverte par un premier revêtement
comprenant un premier médicament, le premier médicament présentant un premier profil
d'élution basé sur le premier revêtement, et
une surface abluminale dont au moins une partie est recouverte par un deuxième revêtement
comprenant un deuxième médicament, le deuxième médicament présentant un deuxième profil
d'élution basé sur le deuxième revêtement, le premier profil d'élution étant différent
du deuxième profil d'élution, le premier revêtement étant constitué d'un matériau
de matrice biostable et le deuxième revêtement étant constitué d'un matériau de matrice
biodégradable.
2. Endoprothèse selon la revendication 1, dans laquelle le premier et le deuxième revêtement
sont dépourvus de polymère.
3. Endoprothèse selon la revendication 1, dans laquelle le premier revêtement a une épaisseur
de 200 nm ou moins.
4. Endoprothèse selon la revendication 1, dans laquelle le premier médicament est incorporé
dans le matériau de matrice biostable.
5. Endoprothèse selon la revendication 4, dans laquelle le premier médicament est un
anticoagulant tel que l'héparine.
6. Endoprothèse selon la revendication 1, dans laquelle le deuxième médicament est incorporé
dans le matériau de matrice biodégradable.
7. Endoprothèse selon la revendication 6, dans laquelle le deuxième médicament est un
médicament antiprolifératif choisi parmi le paclitaxel, l'évérolimus, le tacrolimus
et le sirolimus.
8. Endoprothèse selon la revendication 1, dans laquelle le matériau de matrice biostable
comporte des pores interconnectés.
9. Endoprothèse selon la revendication 8, dans laquelle le matériau de matrice biostable
est un métal, un nitrure métallique ou un oxyde métallique, le métal étant choisi
parmi l'argent, le platine, l'or, l'iridium, le zirconium, le titane, le hafnium,
le niobium, le tantale, le ruthénium, et un mélange de ceux-ci, et l'oxyde ou le nitrure
étant choisi parmi l'oxyde ou le nitrure d'iridium, de zirconium, de titane, de hafnium,
de niobium, de tantale, de ruthénium, de platine, et d'un mélange de ceux-ci.
10. Endoprothèse selon la revendication 9, dans laquelle l'oxyde ou le nitrure a une morphologie
de surface globulaire lisse pour améliorer la croissance des cellules endothéliales
sur l'oxyde ou le nitrure.
11. Endoprothèse selon la revendication 1, dans laquelle le matériau de matrice biodégradable
est un métal ou un sel métallique, le métal étant choisi parmi le magnésium, le calcium,
l'aluminium, le fer, le zinc, le titane, et un mélange de ceux-ci, et le sel métallique
étant choisi parmi l'oxyde de magnésium, le fluorure de magnésium, le phosphate tricalcique,
le carbonate de calcium, et un mélange de ceux-ci.
12. Endoprothèse selon la revendication 1, dans laquelle le premier revêtement est constitué
d'un premier matériau de matrice biostable et le deuxième revêtement est constitué
d'un matériau biodégradable et d'un deuxième matériau de matrice biostable entre le
matériau biodégradable et la surface abluminale, le premier et le deuxième matériau
de matrice biostable étant des matériaux identiques ou différents.
13. Procédé de formation d'une endoprothèse, comprenant :
la formation d'un premier revêtement d'un matériau biostable comprenant un premier
médicament sur une surface luminale de l'endoprothèse de telle sorte que le premier
médicament présente un premier profil d'élution basé sur le premier revêtement, et
la formation d'un deuxième revêtement d'un matériau biodégradable comprenant un deuxième
médicament sur une surface abluminale de l'endoprothèse de telle sorte que le deuxième
médicament présente un deuxième profil d'élution basé sur le deuxième revêtement,
le premier profil d'élution étant différent du deuxième profil d'élution.
14. Procédé selon la revendication 13, dans lequel le matériau biostable et le premier
médicament sont codéposés sur la première région par PLD, ou dans lequel le matériau
biodégradable et le deuxième médicament sont codéposés sur la deuxième région par
PLD.
15. Procédé selon la revendication 13, dans lequel le matériau biostable est un métal,
un nitrure métallique ou un oxyde métallique, l'oxyde ou le nitrure métallique étant
choisi parmi l'oxyde ou le nitrure d'iridium, de zirconium, de titane, de hafnium,
de niobium, de tantale, de ruthénium, de platine, et d'un mélange de ceux-ci.